Dynamic and prognostic proteomic associations with FEV1 decline in chronic obstructive pulmonary disease.

Rationale: Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need. Objective: Identify prognostic and dynamic plasma protein biomarkers of COPD progression. Methods: We measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV1 (prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways. Measurements and Main Results: The prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV1. Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins. Conclusion: We identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

Air Pollution Exposure and Interstitial Lung Features in SPIROMICS Participants with Chronic Obstructive Pulmonary Disease.

Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 µg ⋅ m-3 PM2.5, 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Loss of Airway Phylogenetic Diversity Is Associated with Clinical and Pathobiological Markers of Disease Development in Chronic Obstructive Pulmonary Disease.

Rationale: The airway microbiome has the potential to shape chronic obstructive pulmonary disease (COPD) pathogenesis, but its relationship to outcomes in milder disease is unestablished. Objectives: To identify sputum microbiome characteristics associated with markers of COPD in participants of the Subpopulations and Intermediate Outcome Measures of COPD Study (SPIROMICS). Methods: Sputum DNA from 877 participants was analyzed using 16S ribosomal RNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic, and mucoinflammatory markers, including longitudinal lung function trajectory, were examined. Measurements and Main Results: Participant data represented predominantly milder disease (Global Initiative for Chronic Obstructive Lung Disease stage 0-2 obstruction in 732 of 877 participants). Phylogenetic diversity (i.e., range of different species within a sample) correlated positively with baseline lung function, decreased with higher Global Initiative for Chronic Obstructive Lung Disease stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations (P < 0.001). In covariate-adjusted regression models, organisms robustly associated with better lung function included Alloprevotella, Oribacterium, and Veillonella species. Conversely, lower lung function, greater symptoms, and radiographic measures of small airway disease were associated with enrichment in members of Streptococcus, Actinobacillus, Actinomyces, and other genera. Baseline sputum microbiota features were also associated with lung function trajectory during SPIROMICS follow-up (stable/improved, decline, or rapid decline groups). The stable/improved group (slope of FEV1 regression ⩾66th percentile) had greater bacterial diversity at baseline associated with enrichment in Prevotella, Leptotrichia, and Neisseria species. In contrast, the rapid decline group (FEV1 slope ⩽33rd percentile) had significantly lower baseline diversity associated with enrichment in Streptococcus species. Conclusions: In SPIROMICS, baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Preoperative sleep apnea screening protocol reduces medical emergency team activation in patients with atrial fibrillation.

STUDY OBJECTIVES: The association of in-hospital medical emergency team activation (META) among patients with atrial fibrillation (AF) at risk for obstructive sleep apnea (OSA) is unclear. This study evaluates the performance of the DOISNORE50 sleep questionnaire as an OSA screener for patients with AF and determines the prevalence of META among perioperative patients with underlying AF who have a diagnosis or are at risk for OSA. METHODS: A prospective perioperative cohort of 2,926 patients with the diagnosis of AF was assessed for DOISNORE50 questionnaire screening. Propensity-score matching was used to match patients' physical characteristics, comorbidities, length of stay, and inpatient continuous positive airway pressure device usage. META and intensive care unit admissions during the surgical encounter, 30-day hospital readmissions, and 30-day emergency department visits were evaluated. RESULTS: A total of 1,509 out of 2,926 AF patients completed the DOISNORE50 questionnaire and were enrolled in the OSA safety protocol. Following propensity-score matching, there were reduced adjusted odds of META in the screened group of 0.69 (95% confidence interval: 0.48-0.98, P < .001) in comparison to the unscreened group. The adjusted odds of intensive care unit admissions and emergency department visits within 30 days of discharge were statistically lower for the screened group compared with the unscreened group. CONCLUSIONS: Among perioperative AF patients, evidence supports DOISNORE50 screening and implementation of an OSA safety protocol for reduction of META. This study identified decreased odds of META, intensive care unit admissions, and emergency department visits among the screened group. The high-risk and known OSA group showed reduced odds of META following the implementation of an OSA safety protocol. CITATION: Saha AK, Sheehan KN, Xiang KR, et al. Preoperative sleep apnea screening protocol reduces medical emergency team activation in patients with atrial fibrillation. J Clin Sleep Med. 2024;20(5):783-792.

Protein-Protein interactive networks identified in bronchoalveolar lavage of severe compared to nonsevere asthma.

INTRODUCTION: Previous bronchoalveolar lavage fluid (BALF) proteomic analysis has evaluated limited numbers of subjects for only a few proteins of interest, which may differ between asthma and normal controls. Our objective was to examine a more comprehensive inflammatory biomarker panel in quantitative proteomic analysis for a large asthma cohort to identify molecular phenotypes distinguishing severe from nonsevere asthma. METHODS: Bronchoalveolar lavage fluid from 48 severe and 77 nonsevere adult asthma subjects were assessed for 75 inflammatory proteins, normalized to BALF total protein concentration. Validation of BALF differences was sought through equivalent protein analysis of autologous sputum. Subjects' data, stratified by asthma severity, were analysed by standard statistical tests, principal component analysis and 5 machine learning algorithms. RESULTS: The severe group had lower lung function and greater health care utilization. Significantly increased BALF proteins for severe asthma compared to nonsevere asthma were fibroblast growth factor 2 (FGF2), TGFα, IL1Ra, IL2, IL4, CCL8, CCL13 and CXCL7 and significantly decreased were platelet-derived growth factor a-a dimer (PDGFaa), vascular endothelial growth factor (VEGF), interleukin 5 (IL5), CCL17, CCL22, CXCL9 and CXCL10. Four protein differences were replicated in sputum. FGF2, PDGFaa and CXCL7 were independently identified by 5 machine learning algorithms as the most important variables for discriminating severe and nonsevere asthma. Increased and decreased proteins identified for the severe cluster showed significant protein-protein interactions for chemokine and cytokine signalling, growth factor activity, and eosinophil and neutrophil chemotaxis differing between subjects with severe and nonsevere asthma. CONCLUSION: These inflammatory protein results confirm altered airway remodelling and cytokine/chemokine activity recruiting leukocytes into the airways of severe compared to nonsevere asthma as important processes even in stable status.

Lung Structure and Risk of Sleep Apnea in SPIROMICS.

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions. Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers. Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk. Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18). Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk.

Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema. Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Circulating MicroRNAs associated with Bronchodilator Response in Childhood Asthma.

Rationale: Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology. Objective: The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation. Methods: We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into high and low bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N= 277) vs low (N= 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed. Results: We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR=2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways. Conclusion: MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients. Trial registration: LOCCS cohort [ClinicalTrials.gov number: NCT00156819], GACRS cohort [ClinicalTrials.gov number: NCT00021840].

Changes in Lung Volumes with Spirometric Disease Progression in COPD.

Background: Abnormal lung volumes representing air trapping identify the subset of smokers with preserved spirometry who develop spirometric chronic obstructive pulmonary disease (COPD) and adverse outcomes. However, how lung volumes evolve in early COPD as airflow obstruction develops remains unclear. Methods: To establish how lung volumes change with the development of spirometric COPD, we examined lung volumes from the pulmonary function data (seated posture) available in the U.S. Department of Veterans Affairs electronic health records (n=71,356) and lung volumes measured by computed tomography (supine posture) available from the COPD Genetic Epidemiology (COPDGene®) study (n=7969) and the SubPopulations and InterMediate Outcome Measures In COPD Study (SPIROMICS) (n=2552) cohorts, and studied their cross-sectional distributions and longitudinal changes across the airflow obstruction spectrum. Patients with preserved ratio-impaired spirometry (PRISm) were excluded from this analysis. Results: Lung volumes from all 3 cohorts showed similar patterns of distributions and longitudinal changes with worsening airflow obstruction. The distributions for total lung capacity (TLC), vital capacity (VC), and inspiratory capacity (IC) and their patterns of change were nonlinear and included different phases. When stratified by airflow obstruction using Global initiative for chronic Obstructive Lung Disease (GOLD) stages, patients with GOLD 1 (mild) COPD had larger lung volumes (TLC, VC, IC) compared to patients with GOLD 0 (smokers with preserved spirometry) or GOLD 2 (moderate) disease. In longitudinal follow-up of baseline GOLD 0 patients who progressed to spirometric COPD, those with an initially higher TLC and VC developed mild obstruction (GOLD 1) while those with an initially lower TLC and VC developed moderate obstruction (GOLD 2). Conclusions: In COPD, TLC, and VC have biphasic distributions, change in nonlinear fashions as obstruction worsens, and could differentiate those GOLD 0 patients at risk for more rapid spirometric disease progression.

Impact of Bronchiectasis on COPD Severity and Alpha-1 Antitrypsin Deficiency as a Risk Factor in Individuals with a Heavy Smoking History.

Rationale: Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals. Objectives: To characterize the impact of bronchiectasis on COPD and explore alpha-1antitrypsin as a risk factor for bronchiectasis. Methods: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) participants (N=914; ages 40-80 years; ≥20-pack-year smoking) had high-resolution computed tomography (CT) scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding -alpha-1 antitrypsin, SERPINA1, in 835 participants to test for rare variants, focusing on the PiZ genotype (Glu366Lys, rs28929474). Measurements and Main Results: We identified bronchiectasis in 365 (40%) participants, more frequently in women (45% versus 36%, p=0.0045), older participants (mean age=66[standard deviation (SD)=8.3] versus 64[SD=9.1] years, p=0.0083), and those with lower lung function (forced expiratory volume in 1 second [FEV1 ] percentage predicted=66%[SD=27] versus 77%[SD=25], p<0.0001; FEV1 to forced vital capacity [FVC] ratio=0.54[0.17] versus 0.63[SD=0.16], p<0.0001). Participants with bronchiectasis had greater emphysema (%voxels ≤-950 Hounsfield units, 11%[SD=12] versus 6.3%[SD=9], p<0.0001) and parametric response mapping functional small airways disease (26[SD=15] versus 19[SD=15], p<0.0001). Bronchiectasis was more frequent in the combined PiZZ and PiMZ genotype groups compared to those without PiZ, PiS, or other rare pathogenic variants (N=21 of 40 [52%] versus N=283 of 707[40%], odds ratio [OR]=1.97; 95% confidence interval [CI]=1.002, 3.90, p=0.049), an association attributed to White individuals (OR=1.98; 95%CI = 0.9956, 3.9; p=0.051). Conclusions: Bronchiectasis was common in those with heavy smoking histories and was associated with detrimental clinical and radiographic outcomes. Our findings support alpha-1antitrypsin guideline recommendations to screen for alpha-1 antitrypsin deficiency in an appropriate bronchiectasis subgroup with a significant smoking history.

A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD.

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.

Association of Occupational Exposures and Chronic Obstructive Pulmonary Disease Morbidity.

OBJECTIVE: The aim of the study is to determine whether aggregate measures of occupational exposures are associated with chronic obstructive pulmonary disease (COPD) outcomes in the Subpopulations and Intermediate Outcome Measures in COPD study cohort. METHODS: Individuals were assigned to six predetermined exposure hazard categories based on self-reported employment history. Multivariable regression, adjusted for age, sex, race, current smoking status, and smoking pack-years determined the association of such exposures to odds of COPD and morbidity measures. We compared these with the results of a single summary question regarding occupational exposure. RESULTS: A total of 2772 individuals were included. Some exposure estimates, including "gases and vapors" and "dust and fumes" exposures resulted in associations with effect estimates over two times the estimated effect size when compared with a single summary question. CONCLUSIONS: Use of occupational hazard categories can identify important associations with COPD morbidity while use of single-point measures may underestimate important differences in health risks.

Ambient Air Pollution Exposure and Sleep Quality in COPD.

Rationale: Ambient air pollution exposure is associated with respiratory morbidity among individuals with chronic obstructive pulmonary disease (COPD), particularly among those with concomitant obesity. Although people with COPD report high incidence of poor sleep quality, no studies have evaluated the association between air pollution exposure, obesity, and sleep disturbances in COPD. Methods: We analyzed data collected from current and former smokers with COPD enrolled in the Subpopulations and Intermediate Outcome Measures in COPD -Air Pollution ancillary study (SPIROMICS AIR). Socio-demographics and anthropometric measurements were collected, and 1-year mean historical ambient particulate matter (PM2.5) and ozone concentrations at participants' residences were estimated by cohort-specific spatiotemporal modeling. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI), and regression models were constructed to determine the association of 1-year PM2.5 (1Yr-PM2.5) and 1-year ozone (1Yr-ozone) with the PSQI score, and whether obesity modified the association. Results: In 1308 participants (age: 65.8±7.8 years, 42% women), results of regression analyses suggest that each 10µg/m3 increase in 1Yr-PM2.5 was associated with a 2.1-point increase in PSQI (P=0.03). Obesity modified the association between 1Yr-PM2.5 and PSQI (P=0.03). In obese and overweight participants, a 10µg/m3 increase in 1Yr-PM2.5 was associated with a higher PSQI (4.0 points, P<0.01, and 3.4 points, P<0.01, respectively); but no association in lean-normal weight participants (P=0.51). There was no association between 1 Yr-ozone and PSQI. Conclusions: Overweight and obese individuals with COPD appear to be susceptible to the effects of ambient PM2.5 on sleep quality. In COPD, weight and ambient PM2.5 may be modifiable risk factors to improve sleep quality.

Bronchodilator Responsiveness in Tobacco-Exposed People With or Without COPD.

BACKGROUND: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features. RESEARCH QUESTION: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD? STUDY DESIGN AND METHODS: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV1 (FEV1-BDR), change in FVC (FVC-BDR), and change in in FEV1, FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD). RESULTS: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV1-BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group. INTERPRETATION: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Prolonged, physiologically relevant nicotine concentrations in the airways of smokers.

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8-10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70-850 ng/mL (∼0.5-5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.

NHLBI ASTHMA NETWORKS: IMPROVING PATIENT CARE, MOVING TOWARD PERSONALIZED MEDICINE.

The first NHLBI Clinical Trials Research Network was the Asthma Clinical Research Network (ACRN 1), which was born in 1993 to perform multiple controlled clinical trials for asthma: "… dispassionately examine new & existing therapies for asthma" and "… rapidly communicate findings to medical community," and therefore, to perform clinical trials drug companies could not or would not do. Among the many areas studied by the ACRN and its successor networks, through 2019, was how to effectively and safely use long-acting beta-agonists and to find novel alternatives for them. In its Tiotropium Add-On Trial (TALC) trial, the ACRN demonstrated that tiotropium as add on-therapy to inhaled corticosteroids (ICS) was effective and non-inferior to long-acting beta-agonist add on-therapy. During the lifetime of the clinical trial networks (1993-2020), 71 manuscripts including 25 major clinical trials were published, many which have laid the groundwork for precision approaches for asthma therapy and the now ongoing PrecISE Asthma Network.

A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts.

Introduction: Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting ß2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology. Methods: We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts. Results: A total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p<5×10-8). Performing fine mapping and using a threshold of p<5×10-6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age-genotype interaction effects. Conclusion: Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR.